Mucosal effector memory CD8 T cells (TEM) are located at mucosal epithelium and have a heightened and immediate effector function. By contrast, memory T cells residing within lymphoid tissues and require proliferation and differentiation to become effector cells that migrate to epithelial surfaces. The accumulation of TEM at the pathogen entry site(s) is essential for protective immunity, but the mechanisms that drive the differentiation of mucosal memory cells are poorly understood. Our preliminary data indicate that activation-induced CD8aa, induced by high affinity/avidity TCR signals, might selectively rescue thymocytes and mature CD8 T cells from activation induced cell death (AICD) allowing them to become memory T cells. Furthermore, our data also suggest that the high-affinity CD8aa ligand, the mouse thymus leukemia (TL) antigen, induced on some APCs and constitutively expressed on intestinal epithelial cells, might serve as a second selective key component to assure the long-term accumulation of the fittest effector cells (CD8aa+) to form mucosal TEM. The current proposal is designed to provide solid evidence for these exciting, breakthrough and highly significant initial observations.